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Year : 2010  |  Volume : 47  |  Issue : 2  |  Page : 134-138

Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons

Division of Pediatric Hematology-Oncology, Advanced Pediatric Center, PGIMER, Chandigarh, India

Date of Web Publication5-May-2010

Correspondence Address:
R K Marwaha
Division of Pediatric Hematology-Oncology, Advanced Pediatric Center, PGIMER, Chandigarh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.63002

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 » Abstract 

Background : Relapse of disease is documented in 15-20% of children with acute lymphoblastic leukemia (ALL). Although testicular relapse is rare with modern risk-adapted treatment protocols, earlier, the testes were a frequently encountered site of relapse and were designated as "drug sanctuaries". Purpose : This descriptive study was designed to assess the pattern of testicular relapse and to identify high-risk factors. Materials and Methods : Data obtained from case records of 407 boys with ALL were analyzed. Fine needle aspiration cytology was carried out in children presenting with painless enlargement of testi(e)s. Bone marrow aspiration and cerebrospinal fluid examination were performed concomitantly to confirm or exclude disease at these sites. Results : Testicular relapse was documented in 30 boys. It was isolated in 17 patients and associated with bone marrow and/or central nervous system relapse in 13. At relapse, nine boys were over the age of 10 years. The majority were very early and early relapsers. Hyperleucocytosis was documented in five of 30 and seven of 137 relapsers and nonrelapsers, respectively (P = 0.04). Twelve of the 30 boys with testicular relapse were treated with testicular irradiation, reinduction and maintenance therapy. The estimated median overall survival was 33 months. Conclusion : Testicular relapse, which depends on the therapy administered, may manifest several months/years after completion of treatment. The high incidence of testicular relapse in our series implicates the need of revaluation of our protocol and incorporation of high/intermediate dose methotrexate therapy upfront.

Keywords: Prognostic factors, relapse, testis

How to cite this article:
Kulkarni K P, Marwaha R K, Trehan A, Bansal D. Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons. Indian J Cancer 2010;47:134-8

How to cite this URL:
Kulkarni K P, Marwaha R K, Trehan A, Bansal D. Testicular relapse in childhood acute lymphoblastic leukemia: The challenges and lessons. Indian J Cancer [serial online] 2010 [cited 2022 Dec 2];47:134-8. Available from:

 » Introduction Top

Improvement in the therapy for childhood acute lymphoblastic leukemia (ALL) has led to a dramatic increase in cure rates of >80% over the past few decades. However, relapse of disease is observed in 15-20% of the children with ALL. [1] Bone marrow is the most common site of relapse. [2] Other frequently encountered relapse sites are the central nervous system (CNS) and the testis. [3],[4] The latter, in a large measure, used to account for significantly lower survival rates in male children. With the use of modern risk-stratified chemotherapy, the incidence of testicular relapse has declined notably. [5],[6],[7] In this communication, we share our experience of managing children with relapse of disease in the testis.

 » Materials and Methods Top

This descriptive study is a retrospective analysis of case records of children, aged 1-14 years, with ALL registered in the Pediatric Oncology Clinic of the institute in the period between January 1990 and December 2006.

Data obtained from case records of patients with ALL were analyzed. Information regarding diagnosis, management and outcome were recorded in a predesigned proforma. Follow-up data were as of December 31, 2007. The conduct of the study was approved by the Ethics Review Committee of PGIMER.

Relapse of disease was clinically diagnosed in children presenting with painless enlargement of the testis. The diagnosis of leukemic infiltrates was established by fine needle aspiration cytology. All patients with testicular relapse underwent examination of bone marrow aspirate and cerebrospinal fluid (CSF). The presence of blast cells in the peripheral smear or a blast cell count of >5% in the marrow aspirate denoted hematological relapse. The presence of blasts in a nontraumatic, cytospin specimen of CSF was designated as a CNS relapse. Testicular relapse could be isolated or combined.

Treatment protocol

The treatment protocol used for initial therapy was a modification of the UKALL X protocol. Remission induction chemotherapy consisted of vincristine, prednisolone, l-asparaginase and intrathecal methotrexate (mtx). All patients received either an early or an early and late consolidation phase. CNS prophylactic therapy comprised six doses of intrathecal mtx and cranial irradiation 18 Gray in 10 fractions. The maintenance therapy included daily oral 6-mercaptopurine, weekly dose of oral mtx and 4-weekly pulse of vincristine with prednisolone or dexamethasone. The total duration of therapy was 27 months after attaining complete remission (CR). Intermediate or high-dose systemic mtx was not used in this treatment protocol.

Patients with isolated testicular relapse were treated with reinduction therapy, testicular irradiation and maintenance chemotherapy. The remission induction therapy included vincristine and dexamethasone along with intrathecal mtx. The maintenance therapy consisted of daily oral 6-mercaptopurine, oral mtx (weekly) and 4-weekly pulses of vincristine with prednisolone. The total duration of maintenance therapy was 24-30 months. Consolidation therapy and cranial irradiation were not administered during retreatment.

Testiclar irradiation

Radiotherapy was administered bilaterally to the testis and inguinal canals using a megavoltage device. Testes were irradiated using a solitary port encompassing the scrotal skin inferiorly and laterally. A total dose of 2,400 cGy was administered in eight to 10 fractions. If clinical testicular enlargement persisted after completion of the above radiotherapy, an additional 600 cGy was administered in two to three fractions.


The following criteria were used to define the status of the patients at the time of analysis: CR - an asymptomatic patient with no organomegaly, normal peripheral blood counts and marrow blasts <5%.

Cure - a patient in sustained CR for >6 years.

Survivor - A patient who has completed therapy but is in sustained CR for <6 years

Overall survival (OS) - the percentage of patients who have survived for a defined period of time.

Relapse was classified as very early when it occurred within 18 months of diagnosis, early when it was documented after 18 months but <6 months after completion of therapy and late when it was observed >6 months beyond the end of treatment.

Statistical analysis

Percentage, mean and range were used to describe continuous and categorical variables, respectively. Quantitative variables were compared using analysis of variance (ANOVA) to identify variables that had a significant association with relapse. These were then subjected to multivariate regression analysis to identify the significant predictors for relapse. A "P"-value of <0.05 was taken as significant. The Kaplan-Meier method was used to estimate the OS.

 » Results Top

Of the 407 boys treated for ALL, relapse of disease in the testis (isolated or combined) was recorded in 30 (n = 7.4%) patients [Figure 1]. If patients who were lost to follow-up and therapy defaulters (n = 90) are excluded, the figure rises to 9.5%. Testicular relapse constituted 27.0% (n = 30) of the 111 boys with relapse [Figure 1]. It was isolated in 17 (15.3%) and in combination with other sites in 13 patients [Figure 1].

The mean diagnosis relapse interval (DRI) for testicular relapse (either alone or in combination) was 31.9 ± 4.4 months (range, 12-55 months). The pattern of relapsers is depicted in [Table 1]. Early relapse was documented in 16 (53.3%) patients; 10 of these children had relapsed within 1-6 months of completing therapy, with a mean DRI of 29.7 ± 2.8 months. The mean DRI in eight very early and six late relapsers was 14.5 ± 2.4 and 45 ± 3.2 months, respectively.

The salient clinical and laboratory features of patients with testicular relapse are depicted in [Table 2]. The mean age, white cell count (WCC) and platelet count at presentation in patients with isolated testicular and testicular with bone marrow and/or CNS relapse were compared and the differences were found to be nonsignificant (P = 0.23, P = 0.38 and P = 0.75, respectively). Similarly, none of the above parameters was significantly associated with relapse by multivariate analysis.

Salient characteristics in patients with a testicular relapse (n = 30) and patients in continuous CR (n = 137: 64 cures, 47 survivors and 26 patients in sustained CR for >18 months) were compared. It is evident from [Table 3] that the differences in the mean age, bulk disease, platelet count and WCC were not statistically significant. Hyperleucocytosis was documented in five of 30 (23.3%) relapsers and seven of 137 (5.1%) nonrelapsers (P = 0.04).

Bulk disease, defined as one or more of the following: enlarged lymph node (>2cm), hepatomegaly (>5 cm) and splenomegaly (>5cm), at initial diagnosis was documented in 11 of the 17 cases with isolated testicular relapse. The mean WCC at presentation in these patients was 55.2 ± 36.2Χ10 9 /L (range, 1.6-214.0Χ10 9 /L) [Table 2]. The mean WCC at initial presentation was significantly higher in children with isolated testicular relapse as compared to nonrelapsers (n = 137) (P = 0.03).

Testicular irradiation, reinduction and standard maintenance therapy were used to treat 12 of the 17 boys with isolated testicular relapse, six of whom are still under treatment [Figure 1]. Eighteen opted for no therapy, which included 12 patients who had combined relapse [Figure 1]. The estimated median OS in 30 patients with testicular relapse using the Kaplan-Meier method was 33 months [Figure 2].

 » Discussion Top

Earlier, chemotherapy agents used for treatment of ALL in children were deemed to be unable to penetrate the blood-testicular barrier. Hence, the testes were designated as a "drug sanctuary." Relapse of disease in the testis in boys treated for ALL was considered an ominous event, especially if associated with relapse at other sites such as bone marrow and/or CNS. In the current era, with the advent of risk-adapted therapy protocols and high-dose mtx therapy, there has been a substantial reduction in the incidence of testicular relapse. [5],[6],[7] Moreover, the most important prognostic factor in the current management of ALL is type of treatment received at presentation. Our study was designed to assess the clinical and investigational profile of patients with testicular relapse and their outcome in a cohort of 532 patients treated with a single protocol over a period of 17 years.

Relapse was documented in 23.8% (n = 127) of the cases in our series, of whom 111 were documented in boys. In contrast to data stemming from resource-rich nations, we observed a substantially higher number of relapses, which also manifest as testicular relapse. [1],[5],[6],[7] There were 30 (23.6%) instances of testicular relapse. It was isolated in 17 (15.3%) patients. Data pertaining to testicular relapse from the Indian subcontinent is scant. [8],[9],[10] In a series of reports over different time periods, Advani et al. observed that testicular relapse constituted 4.1%, 8.2% and 14.2% (isolated in 7.1%) of the relapsers. [11],[12],[13] Silverman et al. and Chessels et al. found that testicular relapse constituted 8.5 and 14.9% of the relapsers, respectively. [14],[15] Relapse was confined to the testis in 4.3 and 10.1%, respectively. [14],[15]

Testicular relapse occurred in 7.4% of the boys who received therapy. In contrast, recent data from Mumbai, India, have reported a 3.2% incidence of testicular relapse. Data emanating from developed nations indicate a very low (<2.8%) frequency of testicular relapse. [5],[6],[7],[16] The unequivocally high prevalence rate of testicular relapse in our study cohort prompted analysis of some salient patient characteristics at initial presentation.

Comparative analysis of mean age, bulk disease, platelet and WCC in patients with testicular relapse and those in continuous CR revealed that the differences were not statistically significant. A similar analysis was carried out in those with isolated testicular relapse and those with relapse at multiple sites. The differences were not significant. Hyperleucocytosis was observed in a significantly higher proportion of patients with testicular relapse as compared to nonrelapsers. In comparison to nonrelapsers, patients with isolated testicular relapse had a significantly higher mean WCC. The small series precludes the identification of high-risk factors that could predict a testicular relapse. Moreover, the controversy concerning pathogenesis of testicular relapse remains to be resolved. Investigators have suggested the role of various intratesticular factors, testicular interstitium, blood testicular barrier and its pubertal maturation in regulating testicular lymphoblastic proliferation (which may subsequently manifest as relapse) and rendering cytotoxic drugs ineffective. [17]

Although six patients relapsed >6 months after completion of therapy, the majority were very early and early relapsers. Introduction of intermediate and high-dose mtx in the management of ALL worldover has substantially reduced the incidence of testicular relapse and trounce the blood testicular barrier. [5],[6],[7] This indicates the need of reappraisal of our protocol of treatment and incorporation of intermediate/high-dose mtx as a frontline prophylaxis for testicular relapse.

Survival rates post relapse are dismal, especially if testicular relapse is associated with a hematological relapse. Loss to follow-up and therapy abandonment is common after relapse. Only seven patients are on treatment and active follow-up. However, recent data from India indicate good outcome after testicular relapse. Investigators from Mumbai, India, have reported a 66.7% OS at 10 years after isolated testicular relapse with intensive testicular therapy, testicular irradiation and CNS prophylaxis. [17] Investigators from the Children's Onclology Study Group have documented an over-60% survival after testicular relapse (both isolated and combined). [18] Improvement in post relapse survival rates at our institute necessitates administration of appropriate and aggressive chemotherapy and radiotherapy.

In conclusion, testicular relapses are difficult to predict and often manifest several months/years after completion of treatment. Risk factors are difficult to define although a high WCC and older age (>10 years) at presentation have been cited as possible indicators. In most developing countries, once a patient relapses (even if it is a good risk patient like the one with isolated testicular relapse), it is very difficult to salvage the patient because of socioeconomic reasons. Thus, it is imperative to give the best treatment up-front.

 » References Top

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3.Chessells JM. Relapsed Lymphoblastic Leukaemia in children: A continuing challenge. Br J Haematol 1998;102:423-38.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Chessells JM, Veys P, Kempski H, Henley P, Leiper A, Webb D, et al. Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 2003;123:396-405.  Back to cited text no. 4  [PUBMED]    
5.Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG, et al. Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 1998;92:411-5.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Brecher ML, Weinberg V, Boyett JM, Sinks LF, Jones B, Glicksman A, et al. Intermediate dose methotrexate in childhood acute lymphoblastic leukemia resulting in decreased incidence of testicular relapse. Cancer 1986;58:1024-8.  Back to cited text no. 6  [PUBMED]    
7.DÖrdelmann M, Reiter A, Zimmermann M, Fengler R, Henze G, Riehm H, et al. Intermediate dose methotrexate is as effective as high dose methotrexate in preventing isolated testicular relapse in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1998;20:444-50.  Back to cited text no. 7      
8.Shanta V, Maitreyan V, Sagar TG, Gajalakshmi CK, Rajalekshmy KR. Prognostic variables and survival in pediatric acute lymphoblastic leukemias: Cancer Institute experience. Pediatr Hematol Oncol 1996;13:205-16.  Back to cited text no. 8  [PUBMED]    
9.Vaidya SJ, Advani SH, Pai SK, Nair CN, Kurkure PA, Saikia TK, et al. Survival of childhood acute lymphoblastic leukemia: Results of therapy at Tata Memorial Hospital, Bombay, India. Leuk Lymphoma 1996;20:311-5.   Back to cited text no. 9  [PUBMED]    
10.Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period. Eur J Cancer 2005;41:1570-83.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
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12.Advani SH, Iyer RS, Pai SK, Gopal R, Saikia TK, Nair CN, et al. Four-agent induction/consolidation therapy for childhood acute lymphoblastic leukemia: An Indian experience. Am J Hematol 1992;39:242-8.   Back to cited text no. 12  [PUBMED]    
13.Advani S, Pai S, Venzon D, Adde M, Kurkure PK, Nair CN, et al. Acute lymphoblastic leukaemia in India: An analysis of prognostic factors using a single treatment regimen. Ann Oncol 1999;10:167-76.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Chessells JM, Bailey C, Richards SM. Intensification of treatment and survival in children with lymphoblastic leukaemia: Results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia. Lancet 1995;345:143-8.  Back to cited text no. 14  [PUBMED]    
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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]

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